This project focuses on the role of signal transduction mechanisms in hippocampal Long-term Potentiation (LTP) and memory formation. In the most recent Project Period we have been exploring the role of the Mitogen-Activated Protein Kinase (MAPK) family of signal transduction cascades in hippocampal synaptic plasticity and learning, focusing on the mechanisms through which this pathway controls memory-associated gene transcription. We initiated our studies in this area about 15 years ago by determining that the Extracellular-Signal Regulated Kinase (ERK) isoforms of MAPK are necessary for NMDA receptor-dependent LTP in area CA1. We then transitioned to studies in the behaving animal and discovered that ERK is activated in the hippocampus with contextual associative conditioning, and that ERK activation is necessary for fear conditioning and for spatial learning in the Morris water maze. Studies from a wide variety of laboratories have now shown that MAPK signaling is involved in many forms of synaptic plasticity and learning, in essentially every species that has so far been examined including humans. Given the clear importance of understanding the roles and regulation of ERK in synaptic plasticity and learning, for the next Project Period we propose to continue our investigations into the genomic and epigenomic targets of ERK in the hippocampus. We will pursue the following three Specific Aims: 1: To test the hypothesis that the ERK/MSK pathway regulates histone methylation in the hippocampus. 2: To test the hypothesis that alterations in hippocampal histone methylation occur with memory formation and are necessary for long-term memory and LTP. 3: To test the hypothesis that inhibition of histone de-methylation augments memory formation. By focusing on this important new target for the ERK pathway in hippocampus, histone methylation, we will continue to formulate a comprehensive model of ERK involvement in molecular decision-making in synaptic plasticity and memory.